The objectives of this proposal are to continue the development of transition metal-catalyzed [2+2+2]cycloadditions of unsaturated moieties to generate polycyclic frameworks with potential physiological activity. The specific aims are to use highly reactive forms of cyclopentadienylcobalt to effect low temperature cyclizations of alkynes and nitriles to give specifically substituted arenes and heteroarenes, including aromatic steroids and ergot alkaloids. The cyclization of specifically constructed enediynes should open up ready access to the natural product illudol and the provitamin D nucleus. The recent discovery that the aromatic double bond of indole, pyrrole, imidazole, and furan can be incorporated into this cycloaddition methodology will be exploited in synthetic approaches to lycorane, the aspidosperma alkaloids, the ergot alkaloids, thebaine, strychnine, and other polyheterocycles. The discovery that Alpha,Omega-diynes can be cocyclized with alkenes should provide a general synthetic solution to the problem of linear annelation, a strategy that will be applied to the anthracycline aglycons. Exploratory work will be initiated aimed at incorporating new unsaturated units into this methodology, including C-N, C-O, and allene double bonds. Finally, recently developed syntheses of chiral and optically active cyclopentadienyl ligands should enable their application in transition metal-catalyzed enantioselective transformations, in particular C-C bond formations and hydrogenations.